Nonmelanoma skin cancer (NMSC) is an increasing problem in the world. Basal cell carcinoma (BCC) is the most common type of NMSC, and most frequently occurs in people with fair skin (Marks, R. Cancer 1995, 75, 607). Photodynamic therapy (PDT), a noninvasive treatment and with excellent cosmetic results, is used for the prevention and treatment of BCC cells (Grapengiesser, S.; Ericson, M.; Gudmundsson, F. Clin. Exp. Dermatol. 2002, 27, 493). It employs a combination of a photosensitizing agent and light (Kiesslich, T.; Krammer, B.; Plaetzer, K. Curr. Med. Chem. 2006, 13, 2189). Light activation of a photosensitizer accumulates in the tumor, and in the presence of molecular oxygen, leads to reactive oxygen species (ROS) generation, which ultimately kills the target cells (Dolmans, D. E.; Fukumura, D.; Jain, R. K. Cancer 2003, 3, 380). Nevertheless, reported cure rates vary, and the transdermal penetration levels for both the photosensitizer and its activating light source are listed as limiting factors. These limitations have prompted the research for new photosensitizers.
2-Phenylbenzothiazoles (FIG. 1) represent a novel class of potent and selective antitumor agents (Bradshaw, T. D.; Wrigley, S.; Shi, D-F.; Schultz, R. J.; Paull, K. D.; Stevens, M. F. G. Br. J. Cancer 1998, 77, 745). For instance, 2-(4-aminophenyl)benzothiazoles (Formula 6, Scheme 1) were originally prepared as synthetic intermediates within a programme to design potential tyrosine kinase inhibitors modeled on structural comparisons with the flavone quercetin and the isoflavone genistein, which compete at the ATP-binding sites of tyrosine kinases (Stevens, M. F. G.; McCall, C. J.; Lelieveld, P.; Alexander, P.; Richter, A.; Davies, D. E. J. Med. Chem. 1994, 37, 1689). However, other biological profiles may also be involved in this complicated biological phenomenon and further investigation is needed to address this issue.
Mitochondria are well known to participate actively in the production of ROS which might be harmful if produced excessively, and are critically involved in the regulation of cell death pathways (Gogvadze; Zhivotovsky, B. J. Bioenerg. Biomembr. 2007, 39, 23). Permeabilization of the mitochondrial outer membrane and subsequent release of proapoptotic proteins from the intermembrane space are viewed as decisive events in the initiation and/or execution of apoptosis (Crompton, M. Biochem. J. 1999, 341, 233). In addition, recent evidence has indicated that ROS play a pivotal role in UVA-induced cell damage (Valencia, A.; Kochevar, I. E. Free Radic. Biol. Med. 2006, 40, 641). Consequently, cell death induced by UVA-activated Formula 6 might be correlated with mitochondrial depolarization. The mitogen-activated protein kinase (MAPK) family consists of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK. JNK and p38 MAPK pathways are known to be activated by a variety of environmental stresses and chemicals (Roulston, A.; Reinhard, C.; Amiri, P.; Williams, L. T. J. Biol. Chem. 1998, 273, 10232), while the ERK cascade is activated by mitogenic stimuli and is critical for proliferation and survival (Nagata, Y.; Todokoro, K. Blood 1999, 94, 853). However, ERK signaling has been suggested to be proapoptotic in cells undergoing apoptosis (Xiao, D.; Singh, S. V. Cancer Res. 2002, 62, 3615).